ABSTRACT There has recently been tremendous progress in the treatment of multiple myeloma (MM). Currently effective therapeutics include proteasome inhibitors (PIs) such as bortezomib and carfilzomib and immunomodulatory drugs (IMiDs) such as lenalidomide, and pomalidomide. It has been found that combination therapy with doublet or triplet combinations of drugs with different mechanisms of actions is superior to monotherapy. Even with these advances, multiple myeloma remains mostly incurable, giving rise to a continuous search for new agents with different mechanisms of action and in different combinations, that could prove more effective against drug resistant disease. We now propose to develop and characterize a therapeutic, anti-CD138-IFN?2, with a novel mechanism of action to add to the therapeutic options for combination therapy. Anti-CD138- IFN?2 consists of an antibody recognizing CD138, an antigen expressed on virtually all myeloma cells fused to IFN?2. IFNs have direct cytotoxic effects and are potent regulators of cell growth and the immune response, with proven therapeutic efficacy against many tumors including MM. We have shown that by fusing IFN to an antibody that recognizes an antigen expressed by a tumor, we are able to achieve therapeutically effective doses in the absence of toxicity. We now hypothesize that the anti-CD138-IFN? fusion protein will provide a novel class of therapeutics thus augmenting the currently available treatments and will improve anti-tumor activity when it is included in combination therapies. The goal of the current proposal will be to evaluate the potential of this new therapy to combine with existing therapies for treatment, initially evaluating double treatment, but with the option of moving forward to include multiple agents for treatment. Specifically we will 1). Evaluate the therapeutic efficacy of anti-CD138-IFN?2 in combination with the PIs bortezomib and carfilzomib; and 2). Evaluate the therapeutic efficacy of anti-CD138-IFN?2 in combination with the IMiDs lenalidomide and pomalidomide. For each combination the in vitro anti-tumor activity against a panel of MM cells representing different types of myeloma will initially be evaluated. For selected combinations, the in vivo protection in xenografts will be determined. Combination or synergistic anti-tumor activity in vitro and in vivo will support the fact that anti-CD138-IFN?2 has the possibility of providing an effective new therapy for the treatment of MM.